Dose-Ranging Study of Sofosbuvir in Combination With Pegylated Interferon and Ribavirin in Treatment Naïve GT 1 HCV Patients

Study Description

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Brief Summary:

Participants with genotype 1 HCV infection were randomized to 1 of 3 sofosbuvir doses (100 mg, 200 mg, or 400 mg) or matching placebo once daily based upon stratification for IL28B status (CC or CT/TT). Placebo tablets were administered to participants receiving 100 mg active sofosbuvir (3 placebo tablets) and 200 mg active sofosbuvir (2 placebo tablets) in order to maintain the study blind. Participants received sofosbuvir/matching placebo from Day 0 to 27. Participants also received treatment with PEG+RBV starting on Day 0 of the study which continued for 48 weeks. Participants were evaluated for sustained virologic response (SVR) for an additional 24 weeks following completion of study treatment.

Condition or disease	Intervention/treatment	Phase
Hepatitis C	Drug: Sofosbuvir; Drug: Placebo; Drug: PEG; Drug: RBV	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	64 participants
Allocation:	Randomized
Intervention Model:	Single Group Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Treatment
Official Title:	A Multi-center, Double-Blind, Parallel Group, Randomized, Placebo-Controlled, Dose Ranging Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Following Oral Administration of PSI-7977 in Combination With Standard of Care (Pegylated Interferon and Ribavirin) in Treatment-Naïve Patients With Chronic HCV Infection Genotype 1
Study Start Date :	January 2010
Actual Primary Completion Date :	April 2010
Actual Study Completion Date :	August 2011

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Sofosbuvir 100 mg+PEG+RBV; Participants received sofosbuvir 100 mg (1 x 100 mg tablet) and placebo to match sofosbuvir (3 tablets) for 28 days (baseline to Day 28), plus PEG+RBV (baseline to Week 48)	Drug: Sofosbuvir; Sofosbuvir tablet(s) administered orally once daily; Other Names: Sovaldi®; GS-7977; PSI-7977 Drug: PEG; Pegylated interferon alfa-2a (PEG) 180 μg was administered once weekly by subcutaneous injection.; Other Name: Pegasys® Drug: RBV; Ribavirin (RBV) tablets were administered orally in a divided daily dose according to package insert weight-based dosing recommendations (< 75kg = 1000 mg and ≥ 75 kg = 1200 mg).; Other Name: Copegus®
Experimental: Sofosbuvir 200 mg+PEG+RBV; Participants received sofosbuvir 200 mg (2 x 100 mg tablets) and placebo to match sofosbuvir (2 tablets) for 28 days (baseline to Day 28), plus PEG+RBV (baseline to Week 48)	Drug: Sofosbuvir; Sofosbuvir tablet(s) administered orally once daily; Other Names: Sovaldi®; GS-7977; PSI-7977 Drug: PEG; Pegylated interferon alfa-2a (PEG) 180 μg was administered once weekly by subcutaneous injection.; Other Name: Pegasys® Drug: RBV; Ribavirin (RBV) tablets were administered orally in a divided daily dose according to package insert weight-based dosing recommendations (< 75kg = 1000 mg and ≥ 75 kg = 1200 mg).; Other Name: Copegus®
Experimental: Sofosbuvir 400 mg+PEG+RBV; Participants received sofosbuvir 400 mg (4 x 100 mg tablets) for 28 days (baseline to Day 28), plus PEG+RBV (baseline to Week 48)	Drug: Sofosbuvir; Sofosbuvir tablet(s) administered orally once daily; Other Names: Sovaldi®; GS-7977; PSI-7977 Drug: PEG; Pegylated interferon alfa-2a (PEG) 180 μg was administered once weekly by subcutaneous injection.; Other Name: Pegasys® Drug: RBV; Ribavirin (RBV) tablets were administered orally in a divided daily dose according to package insert weight-based dosing recommendations (< 75kg = 1000 mg and ≥ 75 kg = 1200 mg).; Other Name: Copegus®
Active Comparator: Placebo+PEG+RBV; Participants received placebo to match sofosbuvir (4 tablets) for 28 days (baseline to Day 28), plus PEG+RBV (baseline to Week 48)	Drug: Placebo; Placebo to match sofosbuvir administered orally once daily Drug: PEG; Pegylated interferon alfa-2a (PEG) 180 μg was administered once weekly by subcutaneous injection.; Other Name: Pegasys® Drug: RBV; Ribavirin (RBV) tablets were administered orally in a divided daily dose according to package insert weight-based dosing recommendations (< 75kg = 1000 mg and ≥ 75 kg = 1200 mg).; Other Name: Copegus®

Outcome Measures

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Primary Outcome Measures :

1. Percentage of Participants Who Experienced Adverse Events During the Sofosbuvir Treatment Period [ Time Frame: Baseline to Week 4 ]
   Adverse events (AEs) occurring during the sofosbuvir treatment period were summarized across the participant population. A participant was counted once if they had a qualifying event.

Secondary Outcome Measures :

1. Change in Circulating HCV RNA at Week 4 [ Time Frame: Baseline to Week 4 ]
2. Percentage of Participants With Rapid Virologic Response at Week 4 [ Time Frame: Week 4 ]
   Rapid virologic response (RVR) was defined as HCV RNA below the limit of detection (LOD [15 IU/mL]) at Week 4.
3. Percentage of Participants With Sustained Virologic Response (SVR) at 12 and 24 Weeks After Last Dose of PEG+RBV Following Completion of 48 Weeks of Treatment [ Time Frame: Post-treatment Weeks 12 and 24 ]
   SVR at 12 weeks (SVR12) and 24 weeks (SVR24) was defined as HCV RNA < LOD 12 and 24 weeks after last dose of PEG+RBV, respectively, following completion of 48 weeks of treatment (4 weeks of sofosbuvir or matching placebo and PEG+RBV, followed by an additional 44 weeks of PEG+RBV).
4. Plasma Pharmacokinetics of Sofosbuvir: Cmax at Day 0 [ Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours postdose ]

   The Cmax of sofosbuvir was measured at Day 0 following a single dose of sofosbuvir.

   Cmax is defined as the maximum concentration of drug.

5. Plasma Pharmacokinetics of Sofosbuvir: Cmax at Day 27 [ Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose) ]
   The Cmax of sofosbuvir was measured at Day 27 following continuous dosing of sofosbuvir.
6. Plasma Pharmacokinetics of Sofosbuvir: AUCinf at Day 0 [ Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours postdose ]

   The AUCinf of sofosbuvir was analyzed at Day 0 (following a single dose of sofosbuvir).

   AUCinf is defined as the concentration of drug (area under the plasma concentration versus time curve) extrapolated to infinite time.

7. Plasma Pharmacokinetics of Sofosbuvir: AUCtau at Day 27 [ Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose) ]

   The AUCtau of sofosbuvir was analyzed at Day 27 (following continuous dosing of sofosbuvir).

   AUCtau is defined as the concentration of drug (area under the plasma concentration versus time curve) over the dosing interval.

8. Plasma Pharmacokinetics of GS-331007: Cmax at Day 0 [ Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours postdose ]
   The Cmax of GS-331007 was measured at Day 0 following a single dose of sofosbuvir. GS-331007 is the predominant circulating metabolite of sofosbuvir.
9. Plasma Pharmacokinetics of GS-331007: Cmax at Day 27 [ Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose) ]
   The Cmax of GS-331007 was measured at Day 27 following continuous dosing of sofosbuvir.
10. Plasma Pharmacokinetics of GS-331007: AUCinf at Day 0 [ Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours postdose ]
    The AUCinf of GS-331007 was analyzed at Day 0 (following a single dose of sofosbuvir).
11. Plasma Pharmacokinetics of GS-331007: AUCtau at Day 27 [ Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose) ]
    The AUCtau of GS-331007 was analyzed at Day 27 (following continuous dosing of sofosbuvir).
12. Plasma Pharmacokinetics of GS-566500: Cmax at Day 0 [ Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours postdose ]
    The Cmax of GS-566500 was measured at Day 0 following a single dose of sofosbuvir. GS-566500 is one of the major metabolites of sofosbuvir.
13. Plasma Pharmacokinetics of GS-566500: Cmax at Day 27 [ Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose) ]
    The Cmax of GS-566500 was measured at Day 27 following continuous dosing of sofosbuvir.
14. Plasma Pharmacokinetics of GS-566500: AUCinf at Day 0 [ Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours postdose ]
    The AUCinf of GS-566500 was analyzed at Day 0 (following a single dose of sofosbuvir).
15. Plasma Pharmacokinetics of GS-566500: AUCtau at Day 27 [ Time Frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose) ]
    The AUCtau of GS-566500 was analyzed at Day 27 (following continuous dosing of sofosbuvir).
16. Percentage of Participants Who Developed Resistance to Sofosbuvir [ Time Frame: Baseline to Week 4 ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 65 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Treatment-naive males and females, 18-65 years of age
• Genotype 1 HCV infection
• Negative pregnancy test for females of childbearing age
• Females of childbearing age and males with female partners of childbearing age must use two forms of contraception during treatment and following the last dose of ribavirin in accordance with locally approved label for ribavirin

Exclusion Criteria:

• Hepatitis B or HIV infection
• Pregnant or breast feeding females or male partners of pregnant females
• Previous interferon or ribavirin-based therapy or investigational anti-HCV agent
• History or evidence of medical condition associated with chronic liver disease other than HCV

Contacts and Locations

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Locations

United States, California
Quest Clinical Research
San Francisco, California, United States, 94115
United States, Florida
University of Florida
Gainesville, Florida, United States, 32610
Orlando Immunology Center
Orlando, Florida, United States, 32803
United States, North Carolina
Duke University
Durham, North Carolina, United States, 27710
United States, Texas
Alamo Medical Research Center
San Antonio, Texas, United States, 78215
United States, Washington
Virginia Mason Medical Center
Seattle, Washington, United States, 98101
Puerto Rico
Fundacion de Investigacion de Diego
Santurce, Puerto Rico, 00909

Sponsors and Collaborators

Gilead Sciences

Investigators

Study Director:	Robert H. Hyland, DPhil	Gilead Sciences

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Gilead Sciences
ClinicalTrials.gov Identifier:	NCT01054729 History of Changes
Other Study ID Numbers:	P7977-0221
First Posted:	January 22, 2010
Results First Posted:	February 19, 2014
Last Update Posted:	April 17, 2014
Last Verified:	March 2014

Keywords provided by Gilead Sciences:

Chronic Hepatitis C infection Genotype 1; HCV; GT1; GT 1

Additional relevant MeSH terms:

Hepatitis; Hepatitis C; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections	Interferons; Ribavirin; Sofosbuvir; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action